6-52905797-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000847.5(GSTA3):c.38G>A(p.Arg13Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000422 in 1,610,696 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: GSTA3 NM_000847.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.51

Genes affected

GSTA3 (HGNC:4628): (glutathione S-transferase alpha 3) Cytosolic and membrane-bound forms of glutathione S-transferase are encoded by two distinct supergene families. These enzymes are involved in cellular defense against toxic, carcinogenic, and pharmacologically active electrophilic compounds. At present, eight distinct classes of the soluble cytoplasmic mammalian glutathione S-transferases have been identified: alpha, kappa, mu, omega, pi, sigma, theta and zeta. This gene encodes a glutathione S-tranferase belonging to the alpha class genes that are located in a cluster mapped to chromosome 6. Genes of the alpha class are highly related and encode enzymes with glutathione peroxidase activity. However, during evolution, this alpha class gene diverged accumulating mutations in the active site that resulted in differences in substrate specificity and catalytic activity. The enzyme encoded by this gene catalyzes the double bond isomerization of precursors for progesterone and testosterone during the biosynthesis of steroid hormones. An additional transcript variant has been identified, but its full length sequence has not been determined. [provided by RefSeq, Jul 2008]

LOC105375091 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GSTA3	NM_000847.5	c.38G>A	p.Arg13Gln	missense_variant	2/7	ENST00000211122.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GSTA3	ENST00000211122.4	c.38G>A	p.Arg13Gln	missense_variant	2/7	1	NM_000847.5	P1
GSTA3	ENST00000370968.5	c.-63-2070G>A		intron_variant		1
GSTA3	ENST00000431899.2	c.-61G>A		5_prime_UTR_variant	1/4	5

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151714 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000280 AC: 7 AN: 250318 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135344

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000877

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000425 AC: 62 AN: 1458864 Hom.: 0 Cov.: 27 AF XY: 0.0000441 AC XY: 32 AN XY: 725938

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.0000676

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000405

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 151832 Hom.: 0 Cov.: 31 AF XY: 0.0000539 AC XY: 4 AN XY: 74188

Gnomad4 AFR AF: 0.0000484

Gnomad4 AMR AF: 0.0000657

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 23, 2023

The c.38G>A (p.R13Q) alteration is located in exon 2 (coding exon 1) of the GSTA3 gene. This alteration results from a G to A substitution at nucleotide position 38, causing the arginine (R) at amino acid position 13 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.40
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	0.049
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.25	N
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.0039	T
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	0.80	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.25
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.057	T
Polyphen		0.98	D
Vest4		0.57
MutPred		0.82		Loss of methylation at R13 (P = 0.004);
MVP		0.24
MPC		0.10
ClinPred		0.91	D
GERP RS		2.2
Varity_R		0.71
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs527316722; hg19: chr6-52770595;